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Safety profile of gefitinib in advanced non-small cell lung cancer elderly patients with chronic renal failure: two clinical cases
Lung Cancer (2005) 47, 421—423
SHORT COMMUNICATION
Safety profile of gefitinib in advanced non-small cell lung cancer elderly patients with chronic renal failure: two clinical cases Antonio Rossia, Paolo Maionea, Filomena Del Gaizoa, Ciro Guerrieroa, Vincenzo Castaldob, Cesare Gridellia,∗ a
Unita Operativa di Oncologia Medica, Azienda Ospedaliera “S.G. Moscati”, Via Circumvallazione 68, 83100 Avellino, Italy b Direzione Sanitaria, Azienda Ospedaliera “S.G. Moscati”, Via Circumvallazione 68, 83100 Avellino, Italy KEYWORDS
Summary
Chronic renal failure; Elderly; Gefitinib; Non-small cell lung cancer
Objectives: Comorbidities often contraindicate any chemotherapy in non-small cell lung cancer (NSCLC) patients, even single-agent one. This is the case of chronic renal failure. Methods: Two elderly patients (age >70 years) affected by advanced non-small cell lung cancer and chronic renal failure were treated, as front-line treatment, with gefitinib (ZD1839 — ‘Iressa’) administered orally at the dose of 250 mg daily. Results: In both patients renal function was not impaired by the treatment with gefitinib and no severe toxicity was recorded. One patient reported a stable disease, lasted 141 days, with symptoms relief. In the other patient a mixed response was reported with one large pulmonary site responding to gefitinib, but with appearance of new small lung metastases. He is still alive at 359 days. Conclusions: Gefitinib resulted safety when administered to advanced NSCLC elderly patients affected by chronic renal failure. Gefitinib should be further evaluated as front-line treatment in a larger sample of such patients, in order to establish a therapeutic option for a sort of patients unsuitable for any chemotherapy. © 2004 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
poor Eastern Cooperative Oncology Group performance status (ECOG PS ≥2) and/or advanced age and/or major comorbidities contraindicating standard platinum-based chemotherapy, because of increased risk of severe toxicity [1]. Although for this patient population there is no treatment widely accepted as standard, single-agent chemotherapy with new chemotherapeutic agents such as gemcitabine, vinorelbine and taxanes (the latter espe-
Chemotherapy has a definite palliative role in advanced non-small cell lung cancer (NSCLC). Several advanced NSCLC patients have at diagnosis * Corresponding author. Tel.: +39 0825 203573; fax: +39 0825 203556.
0169-5002/$ — see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2004.09.002
422 cially administered as weekly schedule) can be considered a reasonable alternative option [2]. However, some types of comorbidities, especially if associated with advanced age and/or poor PS, contraindicate any chemotherapy, even singleagent one. This is the case of chronic renal failure. New targeted therapies are often characterized by a more favourable toxicity profile than chemotherapy. The possibility to develop well-tolerated new targeted therapies in such patients is of great interest. Gefitinib (ZD1839 — ‘Iressa’) is an orallyavailable epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, the new targeted agent with the largest amount of clinical data being available on the treatment of advanced NSCLC [3]. The major clinical development of gefitinib has been reported as single-agent therapy in heavily pretreated NSCLC. In fact, single-agent gefitinib has been evaluated in two large randomized phase II trials, named Iressa dose evaluation in advanced lung cancer (IDEAL) 1 and 2, in advanced NSCLC patients pretreated with two or more lines of chemotherapy [4,5]. In these trials, gefitinib, administered at two daily dose-levels (250 and 500 mg), demonstrated to be active with an objective response rate of about 15%, well tolerated and improved cancerrelated symptoms in about 40% of patients. Based on this data gefitinib has been recently licensed for use in 28 countries worldwide. In IDEAL 1 and 2 trials, patients with serum creatinine levels greater than 1.5 times the upper normal limit were not included. As a consequence, data on the feasibility of gefitinib in patients with chronic renal failure lack. In IDEAL 1 and 2 trials, to date the largest clinical studies on single-agent gefitinib published as full papers (209 and 216 patients treated in IDEAL 1 and 2 trials, respectively), no cases of renal toxicity of any grade have been reported. Moreover, the experience from an Expanded Access Programme suggests that gefitinib is well tolerated also in special NSCLC patient populations in which patients with poor PS, major comorbidities or elderly, often characterized by a poorer tolerance to chemotherapy, are included [6]. In a previous paper we reported an excellent safety profile of gefitinib (no grade 3 or 4 adverse events registered) in a special population composed of 59 elderly and/or PS 2 or more patients, treated within a compassionate use programme [7]. Within the above-mentioned programme, we treated with single-agent gefitinib two advanced NSCLC elderly patients, unsuitable for chemotherapy because of chronic renal failure. The patients gave a written informed consent.
A. Rossi et al.
2. Clinical case #1 A 70-year-old man, with a PS 2, was diagnosed having lung squamous cell carcinoma with controlateral lung metastases (stage IV: T2N0M1). The patient was chemotherapy naive due to chronic renal failure and on December 2002, he started treatment with gefitinib administered orally at the dose of 250 mg daily with a baseline creatinine clearance of 24.3 ml/min (serum creatinine level of 2.8 mg/dL) according to Cockroft and Gault formula [8]. The renal function was checked twice weekly, and in more than 4 months of treatment with gefitinib, creatinine clearance ranged between 22 and 26.2 ml/min (serum creatinine levels between 3.1 and 2.6 mg/dL). The EGFR expression was not available because the diagnosis was performed by CTguided fine needle aspiration biopsy. The only sideeffect registered for this patient was grade 1 skin toxicity. Disease stabilization was achieved for a duration of 141 days, associated with symptoms improvement. He died on August 2003 with and overall survival of 259 days.
3. Clinical case #2 In July 2003, a 72-year-old man affected by chronic renal failure and lung adenocarcinoma with mediastinal lymph node and controlateral lung metastases (stage IV: T3N2M1) started, as first-line treatment, oral gefitinib at the dose of 250 mg daily. The PS was 1 and also in this patient the diagnosis was performed by CT-guided fine needle aspiration biopsy so the EGFR expression was not available. The baseline creatinine clearance was 25.9 ml/min (serum creatinine level of 3.1 mg/dL). Renal function was checked twice weekly with creatinine clearance ranging between 21.1 and 33.4 ml/min (serum creatinine levels between 3.75 and 2.36 mg/dL). Treatment resulted very well tolerated with no toxicities of any grade being registered. A mixed response was reported with one large pulmonary site responding to gefitinib, but with appearance of new lung metastases. Treatment with gefitinib, lasted 77 days, was consequently stopped, although a definite clinical benefit had been referred by the patient. At the cut-off date of 30 June 2004, the patient is still alive, with an overall survival of 440 days.
4. Discussion Gefitinib treatment choice for these patients has been based on need of a palliative treatment, on drug pharmacokinetics and on its favorable toxic-
Safety profile of gefitinib in advanced non-small cell lung cancer ity profile. In fact, gefitinib metabolism is hepatic, mainly by the cytochrome P450 isoenzyme CYP 3A4, and its excretion is predominantly via the feces, with renal elimination of drug and metabolites accounting for less than 4% of the administered dose [9]. Moreover, in population based data analyses, no relationships were identified between predicted steady state and creatinine clearance. In both patients renal function was not impaired by therapy with gefitinib and no severe toxicity was recorded. Of interest is that in these patients gefitinib was administered at full dose of 250 mg daily with no dose-reduction or drug discontinuation being needed during treatment. To the best of our knowledge, this is the first report in which gefitinib was administered in patients with chronic renal failure. In our opinion, these experiences, showing its possible excellent safety profile in this clinical condition, candidate gefitinib for a further evaluation as front-line treatment in a larger sample of advanced NSCLC patients affected by chronic renal failure, in order to establish a therapeutic option for a sort of patients otherwise unsuitable for any treatment.
References [1] Pfister DG, Johnson DH, Azzoli CG, Sause V, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment
[2]
[3] [4]
[5]
[6]
[7] [8] [9]
423
of unresectable non-small-cell lung cancer guideline: update 2003 2004;22:330—53. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non small cell lung cancer. The MILES (Multicenter Italian Lung cancer in the Elderly Study) phase 3 randomized trial. J Natl Cancer Inst 2003;95:362— 72. Johnson DH. Gefitinib (Iressa) trials in non-small cell lung cancer. Lung Cancer 2003;41(Suppl 1):S23—8. Fukuoka M, Yano S, Giaccone G, Tamura T, Nagakawa K, Douillard J-Y, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237—46. Kris MG, Natale BR, Herbst RS, Lynch TJ, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149—58. Stahel R, Rossi A, Petruzelka L, Kosmidis P, de Braud F, Bernardo MM, et al. Lessons from the “Iressa” Expanded Access Programme: gefitinib in special non-small-cell lung cancer patient populations. Br J Cancer 2003;89(Suppl 2):S19—23. Gridelli C, Maione P, Castaldo V, Rossi A. Gefitinib in elderly and unfit patients affected by advanced non-small cell lung cancer. Br J Cancer 2003;89:1827—9. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31— 41. Yoshimura M, Imamura F, Ueno K, Yamamto S. Severe myelotoxicity in a combination of gefitinib and vinorelbine. Lung Cancer 2004;45:121—3.
SHORT COMMUNICATION
Safety profile of gefitinib in advanced non-small cell lung cancer elderly patients with chronic renal failure: two clinical cases Antonio Rossia, Paolo Maionea, Filomena Del Gaizoa, Ciro Guerrieroa, Vincenzo Castaldob, Cesare Gridellia,∗ a
Unita Operativa di Oncologia Medica, Azienda Ospedaliera “S.G. Moscati”, Via Circumvallazione 68, 83100 Avellino, Italy b Direzione Sanitaria, Azienda Ospedaliera “S.G. Moscati”, Via Circumvallazione 68, 83100 Avellino, Italy KEYWORDS
Summary
Chronic renal failure; Elderly; Gefitinib; Non-small cell lung cancer
Objectives: Comorbidities often contraindicate any chemotherapy in non-small cell lung cancer (NSCLC) patients, even single-agent one. This is the case of chronic renal failure. Methods: Two elderly patients (age >70 years) affected by advanced non-small cell lung cancer and chronic renal failure were treated, as front-line treatment, with gefitinib (ZD1839 — ‘Iressa’) administered orally at the dose of 250 mg daily. Results: In both patients renal function was not impaired by the treatment with gefitinib and no severe toxicity was recorded. One patient reported a stable disease, lasted 141 days, with symptoms relief. In the other patient a mixed response was reported with one large pulmonary site responding to gefitinib, but with appearance of new small lung metastases. He is still alive at 359 days. Conclusions: Gefitinib resulted safety when administered to advanced NSCLC elderly patients affected by chronic renal failure. Gefitinib should be further evaluated as front-line treatment in a larger sample of such patients, in order to establish a therapeutic option for a sort of patients unsuitable for any chemotherapy. © 2004 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
poor Eastern Cooperative Oncology Group performance status (ECOG PS ≥2) and/or advanced age and/or major comorbidities contraindicating standard platinum-based chemotherapy, because of increased risk of severe toxicity [1]. Although for this patient population there is no treatment widely accepted as standard, single-agent chemotherapy with new chemotherapeutic agents such as gemcitabine, vinorelbine and taxanes (the latter espe-
Chemotherapy has a definite palliative role in advanced non-small cell lung cancer (NSCLC). Several advanced NSCLC patients have at diagnosis * Corresponding author. Tel.: +39 0825 203573; fax: +39 0825 203556.
0169-5002/$ — see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2004.09.002
422 cially administered as weekly schedule) can be considered a reasonable alternative option [2]. However, some types of comorbidities, especially if associated with advanced age and/or poor PS, contraindicate any chemotherapy, even singleagent one. This is the case of chronic renal failure. New targeted therapies are often characterized by a more favourable toxicity profile than chemotherapy. The possibility to develop well-tolerated new targeted therapies in such patients is of great interest. Gefitinib (ZD1839 — ‘Iressa’) is an orallyavailable epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, the new targeted agent with the largest amount of clinical data being available on the treatment of advanced NSCLC [3]. The major clinical development of gefitinib has been reported as single-agent therapy in heavily pretreated NSCLC. In fact, single-agent gefitinib has been evaluated in two large randomized phase II trials, named Iressa dose evaluation in advanced lung cancer (IDEAL) 1 and 2, in advanced NSCLC patients pretreated with two or more lines of chemotherapy [4,5]. In these trials, gefitinib, administered at two daily dose-levels (250 and 500 mg), demonstrated to be active with an objective response rate of about 15%, well tolerated and improved cancerrelated symptoms in about 40% of patients. Based on this data gefitinib has been recently licensed for use in 28 countries worldwide. In IDEAL 1 and 2 trials, patients with serum creatinine levels greater than 1.5 times the upper normal limit were not included. As a consequence, data on the feasibility of gefitinib in patients with chronic renal failure lack. In IDEAL 1 and 2 trials, to date the largest clinical studies on single-agent gefitinib published as full papers (209 and 216 patients treated in IDEAL 1 and 2 trials, respectively), no cases of renal toxicity of any grade have been reported. Moreover, the experience from an Expanded Access Programme suggests that gefitinib is well tolerated also in special NSCLC patient populations in which patients with poor PS, major comorbidities or elderly, often characterized by a poorer tolerance to chemotherapy, are included [6]. In a previous paper we reported an excellent safety profile of gefitinib (no grade 3 or 4 adverse events registered) in a special population composed of 59 elderly and/or PS 2 or more patients, treated within a compassionate use programme [7]. Within the above-mentioned programme, we treated with single-agent gefitinib two advanced NSCLC elderly patients, unsuitable for chemotherapy because of chronic renal failure. The patients gave a written informed consent.
A. Rossi et al.
2. Clinical case #1 A 70-year-old man, with a PS 2, was diagnosed having lung squamous cell carcinoma with controlateral lung metastases (stage IV: T2N0M1). The patient was chemotherapy naive due to chronic renal failure and on December 2002, he started treatment with gefitinib administered orally at the dose of 250 mg daily with a baseline creatinine clearance of 24.3 ml/min (serum creatinine level of 2.8 mg/dL) according to Cockroft and Gault formula [8]. The renal function was checked twice weekly, and in more than 4 months of treatment with gefitinib, creatinine clearance ranged between 22 and 26.2 ml/min (serum creatinine levels between 3.1 and 2.6 mg/dL). The EGFR expression was not available because the diagnosis was performed by CTguided fine needle aspiration biopsy. The only sideeffect registered for this patient was grade 1 skin toxicity. Disease stabilization was achieved for a duration of 141 days, associated with symptoms improvement. He died on August 2003 with and overall survival of 259 days.
3. Clinical case #2 In July 2003, a 72-year-old man affected by chronic renal failure and lung adenocarcinoma with mediastinal lymph node and controlateral lung metastases (stage IV: T3N2M1) started, as first-line treatment, oral gefitinib at the dose of 250 mg daily. The PS was 1 and also in this patient the diagnosis was performed by CT-guided fine needle aspiration biopsy so the EGFR expression was not available. The baseline creatinine clearance was 25.9 ml/min (serum creatinine level of 3.1 mg/dL). Renal function was checked twice weekly with creatinine clearance ranging between 21.1 and 33.4 ml/min (serum creatinine levels between 3.75 and 2.36 mg/dL). Treatment resulted very well tolerated with no toxicities of any grade being registered. A mixed response was reported with one large pulmonary site responding to gefitinib, but with appearance of new lung metastases. Treatment with gefitinib, lasted 77 days, was consequently stopped, although a definite clinical benefit had been referred by the patient. At the cut-off date of 30 June 2004, the patient is still alive, with an overall survival of 440 days.
4. Discussion Gefitinib treatment choice for these patients has been based on need of a palliative treatment, on drug pharmacokinetics and on its favorable toxic-
Safety profile of gefitinib in advanced non-small cell lung cancer ity profile. In fact, gefitinib metabolism is hepatic, mainly by the cytochrome P450 isoenzyme CYP 3A4, and its excretion is predominantly via the feces, with renal elimination of drug and metabolites accounting for less than 4% of the administered dose [9]. Moreover, in population based data analyses, no relationships were identified between predicted steady state and creatinine clearance. In both patients renal function was not impaired by therapy with gefitinib and no severe toxicity was recorded. Of interest is that in these patients gefitinib was administered at full dose of 250 mg daily with no dose-reduction or drug discontinuation being needed during treatment. To the best of our knowledge, this is the first report in which gefitinib was administered in patients with chronic renal failure. In our opinion, these experiences, showing its possible excellent safety profile in this clinical condition, candidate gefitinib for a further evaluation as front-line treatment in a larger sample of advanced NSCLC patients affected by chronic renal failure, in order to establish a therapeutic option for a sort of patients otherwise unsuitable for any treatment.
References [1] Pfister DG, Johnson DH, Azzoli CG, Sause V, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment
[2]
[3] [4]
[5]
[6]
[7] [8] [9]
423
of unresectable non-small-cell lung cancer guideline: update 2003 2004;22:330—53. Gridelli C, Perrone F, Gallo C, Cigolari S, Rossi A, Piantedosi F, et al. Chemotherapy for elderly patients with advanced non small cell lung cancer. The MILES (Multicenter Italian Lung cancer in the Elderly Study) phase 3 randomized trial. J Natl Cancer Inst 2003;95:362— 72. Johnson DH. Gefitinib (Iressa) trials in non-small cell lung cancer. Lung Cancer 2003;41(Suppl 1):S23—8. Fukuoka M, Yano S, Giaccone G, Tamura T, Nagakawa K, Douillard J-Y, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003;21:2237—46. Kris MG, Natale BR, Herbst RS, Lynch TJ, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149—58. Stahel R, Rossi A, Petruzelka L, Kosmidis P, de Braud F, Bernardo MM, et al. Lessons from the “Iressa” Expanded Access Programme: gefitinib in special non-small-cell lung cancer patient populations. Br J Cancer 2003;89(Suppl 2):S19—23. Gridelli C, Maione P, Castaldo V, Rossi A. Gefitinib in elderly and unfit patients affected by advanced non-small cell lung cancer. Br J Cancer 2003;89:1827—9. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31— 41. Yoshimura M, Imamura F, Ueno K, Yamamto S. Severe myelotoxicity in a combination of gefitinib and vinorelbine. Lung Cancer 2004;45:121—3.